Synthesis of 3-deoxy-2-ulosonic acid KDO and 4-epi-KDN, a highly efficient approach of 3-C homologation by propargylation and oxidation

Article abstract of DOI:10.1016/S0040-4020(02)01129-8

Through the introduction of a pyruvate segment by asymmetric propargylation and oxidation of terminal alkynes, both KDO and 4-epi-KDN have been concisely synthesized in the furanose form from readily available sugars in high overall yields.

Full text of DOI:10.1016/S0040-4020(02)01129-8

Tetrahedron 58 (2002) 9049–9054
Synthesis of 3-deoxy-2-ulosonic acid KDO and 4-epi-KDN, a
highly efficient approach of 3-C homologation by propargylation
and oxidation
*
Lian-Sheng Li and Yu-Lin Wu
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, People’s Republic of China
Received 6 June 2002; revised 9 August 2002; accepted 5 September 2002
Abstract—Through the introduction of a pyruvate segment by asymmetric propargylation and oxidation of terminal alkynes, both KDO and
4-epi-KDN have been concisely synthesized in the furanose form from readily available sugars in high overall yields. q 2002 Elsevier
Science Ltd. All rights reserved.
Higher 3-deoxy-2-ulosonic acids, such as 3-deoxy-D-
manno-2-octulosonic acid (KDO, 1) and 3-deoxy-D-
glycero-D-galacto-2-ulosonic acid (KDN, 2), are involved
in a number of biological processes. KDO is an essential
constituent of the outer-cell membrane lipopolysaccharide
(LPS) of Gram-negative bacteria, and incorporation of KDO
is likely to be a key step in the growth of these bacteria.1
KDN is a deaminated sialic acid first isolated in 1986 by
Inoue and co-workers2 from the membrane polysialoglyco-
proteins of rainbow trout eggs. It has been shown that KDN
Figure 1. Retrosynthetic analysis of KDO and KDN.
is likely to be responsible for protection of the egg
membrane from attacks by bacterial sialidases.3 A more
recent discovery shows that free KDN occurs at elevated
levels in human fetal cord red blood cells and ovarian cancer
cells. Thus it can be an early warning signal of disease and a
marker for detecting recurrence of disease.4 Consequently,
more and more attention has been paid to the synthesis of
these ulosonic acids and their analogs5,6 in efforts to develop
potential biologically interesting agents. One of the
challenging problems in the synthesis of such ulosonic
acids is the introduction of the a-keto acid moiety. A
straightforward and efficient way is asymmetric reaction of
a proper aldehyde with a pyruvate equivalent followed by
conversion of the adduct to the a-keto acid ester, which to
some extent is similar to the biosynthesis. Herewith we
would like to describe such a general strategy for the
synthesis of a range of 3-deoxy-2-ulosonic acids based on
the asymmetric propargylation of sugar aldehydes7
developed earlier by us and a subsequent oxidation of the
terminal alkynes8 (Fig. 1).
Our synthetic approach to KDO (1) started with the readily
available D-glucono-a-lactone-derived aldehyde 39
(Scheme 1). Subsequent coupling with 3-bromopropyne
according to the previously described procedure gave the
desired erythro (anti) adduct 47d in good yield (83%). After
protection of the homopropargylic alcohol as a MOM ether,
compound 5 was converted to the corresponding bromo-
alkyne 6 (86% yield) by stirring with N-bromosuccinimide
and silver nitrate at room temperature. Subsequent oxidation
of compound 6 with KMnO4 afforded the key intermediate
a-keto acid ester 7 in 87% yield. It has been shown that
methanolic HCl is a good reagent for deprotection and
cyclization in the synthesis of nonulosonic acid.10 There-
fore, compound 7 was treated with conc. HCl in methanol at
room temperature for 36 h. The generated methyl glycoside
of KDO was then treated with acetic anhydride in pyridine
to produce a ca. 4:1 mixture of anomeric acetates 8. The
major isomer was carefully isolated and fully characterized.
The structure of compound 8 was then unambiguously
assigned to the furanose form by comparison with the data5e
of known corresponding pyranose form compounds, and
especially the chemical shifts of C3-protons (2.63 and 2.34)
also confirmed5r the furanose form of compound 8.
Keywords: carbohydrates; ulosonic acid; KDO; KDN; propargylation;
oxidation.
*
Corresponding author. Fax: þ86-21-64166128;
e-mail: ylwu@pub.sioc.ac.cn
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01129-8

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L.-S. Li, Y.-L. Wu / Tetrahedron 58 (2002) 9049–9054
a-keto ester 14 to the corresponding 4-epi-KDN as furanose
form 15 was carried out smoothly as described above. Then
we briefly examined a sequence for epimerization of the
hydroxy group at C4 as an route to KDN itself.
Unfortunately, a Mitsunobo inversion13 of configuration at
C4 by treatment of 10 with either benzoic acid or 3,5-
dinitrobenzoic acid in the presence of triphenylphosphine
and diethyl azodicarboxylate gave no desired benzoyl
derivative 11, probably due to the steric hindrance caused
by the substituent at C5.
In conclusion, based on the asymmetric propargylation and
oxidation of terminal alkynes, both KDO and 4-epi-KDN in
the furanose form have been synthesized from readily
available sugar aldehydes in 41% and 35% overall yield,
respectively. Further studies on the synthesis of other
3-deoxy-2-ulosonic acids using this strategy are underway
in this laboratory and will be reported in due time.
Scheme 1. Reagents and conditions: (a) Lit9; (b) 3-bromopropyne, DMF–
Et2O, Zn, 83%; (c) MOMCl, Pr2NEt, 08C to rt, 88%; (d) NBS, AgNO3,
acetone, rt, 86%; (e) KMnO4, NaHCO3, MgSO4, MeOH/H2O (1:1), 08C,
87%; (f) conc. HCl, anhydrous MeOH, rt, 2 days, then Ac2O, Py., DMAP,
CH2Cl2, rt, 75% (two steps) (anomeric mixture about 4:1).
i
Considering that the furanose isomers of N-acetyl
neuraminic acid (Neu5Ac) exhibit remarkable inhibitory
activity comparable to the pyranose analogue,11 the KDO
isomer in furanose form we obtained is expected to have
potent biological activity.
1. Experimental
1.1. General considerations
IR spectra were recorded on Perkin–Elmer 983 or
1
Shimadzu IR-440 spectrometers. H and 13C NMR were
Our interest in modified ulosonic acids then led us to explore
application of this methodology to the synthesis of 4-epi-
KDN. Starting from the known 2,3:5,6-di-O-isopropylidene
mannitol12 9a (Scheme 2), selective protection of the
primary alcohol as a t-butyldimethylsilyl ether and treat-
ment with MOMCl followed by removal of the silyl group
by nBu4NF gave the desired primary alcohol 9d (82%
overall yield for three steps). Swern oxidation of 9d
followed by coupling with 3-bromopropyne produced the
desired erythro (anti) adduct 10 in 77% yield (two steps).
Protection of the hydroxy in 10 as a t-butyldimethylsilyl
ether afforded 12, which was converted to the corresponding
a-keto ester 14 by bromination and oxidation reactions
(58% overall yield for three steps). Transformation of
recorded in CDCl3 on an AMX-300, DPX-300 or DRX-400
spectrometers with TMS as the internal standard. Mass
spectra were taken on a HP5973N or HP5989A instrument.
Optical rotations were measured on a Perkin–Elmer 241
MC polarimeter. Elemental analyses were carried out at the
Microanalytic Laboratory of Shanghai Institute of Organic
Chemistry. Flash column chromatography was performed
on silica gel H (10–40 mm) with petroleum ether/ethyl
acetate or ethyl acetate/ethanol as eluent.
1.1.1. 1,2,3-Trideoxy-5,6:7,8-di-O-isopropylidene-D-
manno-1-yno-octitol (4).7d To a vigorously stirred solution
of aldehyde 39 (2.5 g, 10.8 mmol) and 3-bromopropyne
(1.9 g, 15.8 mmol) in anhydrous DMF–Et2O (1:1, 40 mL)
Scheme 2. Reagents and Conditions: (a) (i) Conc. H2SO4, acetone, 82%, (ii) LiAlH4, THF, 92%; (b) TBSCl, DMF, Im., rt, 96%; (c) MOMCl, iPr2NEt, CH2Cl2,
rt, 92%; (d) nBu4NF, THF, 93%; (e) (i) oxalyl chloride, DMSO, Et3N; (ii) 3-bromopropyne, Zn, DMF–Et2O, 77%; (f) TBSCl, DMF, Im., rt, 84%; (g) NBS,
AgNO3, acetone, 87%; (h) KMnO4, NaHCO3, MgSO4, CH3OH/H2O (1:1), 08C, 79%; (i) conc. HCl, anhydrous CH3OH, rt, then Ac2O, Py., DMAP, CH2Cl2, rt,
78% (two steps).

L.-S. Li, Y.-L. Wu / Tetrahedron 58 (2002) 9049–9054
9051
under nitrogen, was slowly added activated zinc dust (1.5 g,
21.6 mmol) in portions. The resulting refluxing mixture was
cooled to room temperature; stirring was continued until
TLC showed the completion of the reaction. Then, the
mixture was poured into saturated aqueous NH4Cl,
extracted with Et2O (50 mL£3). The combined organic
layers were dried over MgSO4, filtered and concentrated.
The residue was purified by column chromatography on
silica gel to afford 4 (2.43 g, 83%). [a]D¼þ11.3 (c, 1.02,
CHCl3). 1H NMR (300 MHz, CDCl3): d 4.22–3.72 (6H, m,
OCH), 2.6–2.4 (2H, m, CH2), 2.05 (1H, t, J¼2.4 Hz,
u–H), 1.46 (3H, s, CH3), 1.42 (3H, s, CH3), 1.38 (6H, s,
CH3). EIMS (m/z, %): 255 (Mþ2Me, 100.0), 173 (19.1),
143 (63.1), 101 (51.6), 59 (96.2), 43 (90.3). IR (film): 3463,
(100 mg, 1.2 mmol) and MgSO4 (480 mg, 4 mmol) in H2O
(30 mL), followed by addition of solid KMnO4 (620 mg,
4 mmol) in portions. The mixture was stirred for 1.5 h at
08C, then poured into 30 mL of ice water and extracted with
EtOAc (50 mL£4). The combined organic phase was
washed with H2O and brine, then dried over MgSO4. The
solvent was removed under reduced pressure, and the
residue was purified by column chromatography on silica
gel to give 7 (650 mg, 87%). [a]D¼þ29.5 (c, 1.3, CHCl3).
1H NMR (300 MHz, CDCl3): d 4.73 (1H, d, J¼6.8 Hz,
OCHHO), 4.69 (1H, d, J¼6.8 Hz, OCHHO), 4.36 (1H, m,
OCH), 4.10 (4H, m, OCH), 3.97 (1H, dd, J¼7.3, 4.4 Hz,
OCH), 3.90 (3H, s, OCH3), 3.88 (1H, m), 3.34 (3H, s,
OCH3), 3.28 (1H, dd, J¼17.1, 7.7 Hz, CHH), 3.12 (1H, dd,
J¼17.1, 4.9 Hz, CHH), 1.44 (3H, s, CH3), 1.40 (3H, s, CH3),
1.38 (3H, s, CH3), 1.35 (3H, s, CH3). 13CNMR (75 MHz,
CDCl3): d 191.2, 161.1, 110.0, 109.7, 97.0, 82.3, 78.5, 77.1,
73.5, 67.7, 55.8, 52.8, 41.8, 27.2, 26.6, 26.4, 25.1. EIMS
(m/z, %): 361 (Mþ2Me, 33.1), 257 (21.4), 199 (26.0), 143
(66.6), 59 (24.6), 45 (100.0). IR (film): 2989, 2938, 2898,
3290, 2989, 2121, 1382, 1216, 1071, 846, 645 cm21
.
1.1.2. 4-O-Methoxymethyl-1,2,3-trideoxy-5,6:7,8-di-O-
isopropylidene-D-manno-1-yno-octitol (5). To a solution
of 4 (2.4 g, 8.9 mmol) in anhydrous CH2Cl2 (30 mL) at 08C
under nitrogen, were added MOMCl (2.8 mL, 35.6 mmol)
i
and Pr2NEt (6.6 mL, 39.2 mmol) dropwise. After stirring
1757, 1733, 1382, 1253, 1215, 1070, 1039, 847 cm21
.
for 30 h at room temperature, the reaction mixture was
diluted with Et2O, washed with water, saturated aqueous
NH4Cl and brine, then dried over MgSO4. After concen-
tration under reduced pressure, the residue was purified by
column chromatography on silica gel (PE/EA¼10:1) to
afford compound 5 (2.24 g, 88%). [a]D¼þ10.5 (c, 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): d 4.84 (1H, d,
J¼6.8 Hz, OCHHO), 4.76 (1H, d, J¼6.8 Hz, OCHHO),
4.20–3.7 (6H, m, OCH), 3.44 (3H, s, OCH3), 2.60 (2H, m,
CH2), 2.03 (1H, t, J¼2.0 Hz, u–H), 1.44 (3H, s, CH3), 1.41
(6H, s, CH3), 1.36 (3H, s, CH3). EIMS (m/z, %): 299
(Mþ2Me, 28.9), 255 (3.7), 143 (60.6), 101 (27.5), 45
(100.0), 43 (57.0). IR (film): 3278, 2994, 2119, 1377, 1156,
Elemental analysis for C17H28O9 Calcd: C 54.26, H 7.45;
Found: C 54.24, H 7.51.
1.1.5. Methyl 4,6,7,8-tetra-O-acetyl-2,5-anhydro-3-
deoxy-2-methoxyl-D-manno-octofuranos-2-ulosonate
(8). To a stirred solution of 7 (165 mg, 0.44 mmol) in
anhydrous methanol (10 mL) at 08C under nitrogen, was
added conc. HCl (0.2 mL). After stirring at room tempera-
ture for 2 days, the reaction mixture was cooled to 08C,
carefully neutralized with solid NaHCO3. The solvent was
evaporated under reduced pressure and the residue was
dissolved in anhydrous CH2Cl2 (3 mL), followed by
addition of Ac2O (1.2 mL), pyridine (1.4 mL) and a
catalytic amount of DMAP. After stirring at room
temperature for 24 h, the reaction mixture was concentrated
under reduced pressure, and purified by column chroma-
tography on silica gel to afford 8 (140 mg, 75%).
1073, 643 cm21
.
1.1.3. 4-O-Methoxymethyl-1-bromo-1,2,3-trideoxy-
5,6:7,8-di-O-isopropylidene-D-manno-1-yno-octitol (6).
To a solution of 5 (1.57 g, 5 mmol) in acetone (20 mL)
under nitrogen, were added AgNO3 (340 mg, 2 mmol) and
NBS (0.90 g, 7.5 mmol). After stirring at room temperature
for 10 h, the reaction mixture was diluted with Et2O, and
then filtered through Celite. The filtrate was concentrated
under reduced pressure; the residue was dissolved in Et2O,
and then washed with H2O, and brine, dried over MgSO4.
The solvent was evaporated under reduced pressure, and the
residue was purified by column chromatography on silica
gel to afford 6 (1.69 g, 86%). [a]D¼þ11.6 (c, 1.1, CHCl3).
1H NMR (300 MHz, CDCl3): d 4.79 (1H, d, J¼6.9 Hz,
OCHHO), 4.75 (1H, d, J¼6.9 Hz, OCHHO), 4.2–3.80 (6H,
m, OCH), 3.43 (3H, s, OCH3), 2.65 (1H, dd, J¼17.3, 5.5 Hz,
CHH), 2.58 (1H, dd, J¼17.3, 6.0 Hz, CHH), 1.43 (3H, s,
CH3), 1.39 (6H, s, CH3), 1.36 (3H, s, CH3). EIMS (m/z, %):
379 (Mþ2Me, 28.6), 377 (Mþ2Me, 28.7), 217 (10.3), 143
(52.8), 101 (28.0), 85 (15.4), 45 (100.0). IR (film): 1988,
1
[a]D¼þ34.5 (c, 0.9, CHCl3). H NMR (300 MHz, C6D6):
d 5.75 (1H, dd, J¼6.1, 3.2 Hz, OCH), 5.69 (1H, dt, J¼2.4,
6.1 Hz, OCH), 5.18 (1H, m, OCH), 4.59 (2H, m, OCH), 4.33
(1H, dd, J¼12.4, 5.6 Hz, OCH), 3.32 (3H, s, OCH3), 3.31
(3H, s, OCH3), 2.63 (1H, dd, J¼14.8, 8.1 Hz, CHH), 2.34
(1H, dd, J¼14.8, 2.7 Hz, CHH), 1.72 (3H, s, CH3COO),
1.68 (3H, s, CH3COO), 1.67 (3H, s, CH3COO), 1.58 (3H, s,
CH3COO). 13C NMR (150 MHz, C6D6): d 170.1, 170.0,
169.6, 169.5, 168.1, 106.7, 83.3, 74.1, 71.1, 70.2, 62.1, 51.9,
51.4, 42.7, 20.4, 20.3, 20.1. EIMS (m/z, %): 403
(Mþ2OMe, 15.8), 375 (84.7), 283 (34.6), 153 (85.8), 43
(100.0). IR (film): 2959, 1744 (broad), 1373, 1213,
1104 cm21. Elemental analysis for C18H26O12 Calcd: C
49.77, H 5.99; Found: C 49.91, H 6.04.
1.1.6. 2,3:5,6-Di-O-isopropylidene-D-mannitol12 (9a). To
a solution of 2,3:5,6-di-O-isopropylidene-D-mannofuranose
(6 g, 23 mmol) in dry THF (100 mL) at 08C, was slowly
added LiAlH4 (965 mg, 25.4 mmol) portion-wise. The
mixture was stirred at rt for 2 h. Then the excess LiAlH4
was carefully destroyed by addition of saturated aqueous
NH4Cl, Celite and Et2O, then stirring was continued for
30 min. Then the suspension was filtered through Celite,
washed with Et2O. The combined filtrate was concentrated
under reduced pressure, and then purified by column
2973, 1456, 1381, 1215, 1154, 1069, 1045, 848 cm21
.
Elemental analysis for C16H25O6Br Calcd: C 48.85, H 6.36;
Found: C 49.03, H 6.32.
1.1.4. Methyl (4-O-methoxymethyl-5,6:7,8-di-O-isopro-
pylidene-D-manno-3-deoxy-2-keto)octonate (7). To a
vigorously stirred solution of 6 (786 mg, 2 mmol) in
MeOH (30 mL) at 08C, was added a solution of NaHCO3

9052
L.-S. Li, Y.-L. Wu / Tetrahedron 58 (2002) 9049–9054
chromatography on silica gel (PE/EA¼1:2) to give diol 9a
(4.84 g, 81%). [a]D¼28.7 (c, 0.6, CHCl3). 1H NMR
(300 MHz, CDCl3): d 4.40 (1H, dd, J¼7.4, 1.5 Hz, OCH),
4.42 (1H, m, OCH), 4.14–4.10 (3H, m, OCH), 3.85 (1H, m,
OCH), 3.60 (1H, t, J¼6.3 Hz, OCH), 3.12 (1H, d, J¼6.3 Hz,
OCH), 2.65 (1H, bt, J¼5.7 Hz, OH), 1.52 (3H, s, CH3), 1.41
(3H, s, CH3), 1.40 (3H, s, CH3), 1.36 (3H, s, CH3). EIMS
(m/z, %): 247 (Mþ2Me, 36.5), 205 (88.1), 147 (100.0), 101
(78.0), 43 (74.2). IR (film): 3427, 2987, 1381, 1216, 1068,
CDCl3): d 4.87 (1H, d, J¼6.8 Hz, OCH2O), 4.74 (1H, d,
J¼6.8 Hz, OCH2O), 4.25–4.03 (4H, m, OCH), 3.94 (1H, t,
J¼7.7 Hz, OCH), 3.86 (1H, t, J¼6.6 Hz, OCH), 3.78 (1H,
m, OCH), 3.66 (1H, dd, J¼11.1, 6.9 Hz, OCH), 3.40 (3H, s,
OCH3), 2.66 (1H, bs, OH), 1.48 (3H, s, CH3), 1.42 (3H, s,
CH3), 1.37 (3H, s, CH3), 1.35 (3H, s, CH3). EIMS (m/z, %):
291 (Mþ2Me, 9.6), 275 (30.3), 217 (55.7), 101 (65.8), 45
(100.0). IR (film): 3475, 2987, 1372, 1219, 1159, 1032,
852 cm21. Elemental analysis for C14H26O7 Calcd: C 54.89,
H 8.55; Found: C 55.14, H 8.53.
851 cm21
.
1.1.7. 1-O-[(t-Butyl)dimethylsilyl]-2,3:5,6-di-O-isopro-
pylidene-D-mannitol (9b). To a solution of diol 9a (4.6 g,
17.5 mmol) in anhydrous DMF (30 mL) at 08C, were added
TBSCl (3.2 g, 21 mmol) and imidazole (3.6 g, 53 mmol).
The mixture was stirred at room temperature for 4 h, then
poured into water (50 mL), extracted with Et2O (40 mL£4).
The combined organic layers were washed with brine, dried
over MgSO4, then filtered, concentrated under reduced
pressure, the residue was purified by column chromato-
graphy on silica gel (PE/EA¼4:1) to give 9b (6.8 g, 96%).
[a]D¼217.6 (c, 0.6, CHCl3). 1H NMR (300 MHz, CDCl3):
d 4.38 (1H, d, J¼7.1 Hz, OCH), 4.25 (1H, dt, J¼3.9, 6.6 Hz,
OCH), 4.15–3.96 (4H, m, OCH, OH), 3.84 (1H, dd, J¼11.0,
3.8 Hz, OCH), 3.68 (1H, m, OCH), 3.20 (1H, d, J¼6.0 Hz,
OCH), 1.50 (3H, s, CH3), 1.40 (3H, s, CH3), 1.39 (3H,
1.1.10. 7-O-Methyoxymethyl-1,2,3-trideoxy-5,6:8,9-di-
O-isopropylidene-D-erythro-D-manno-1-yno-nonitol
(10). To a solution of oxalyl chloride (1.90 mL, 18.6 mmol)
in anhydrous CH2Cl2 (30 mL) stirred at 2788C, was added
DMSO (2.9 mL, 41.5 mmol) in CH2Cl2 (15 mL). The
mixture was stirred at 2788C for 30 min. A solution of
compound 9d (3.8 g, 12.4 mmol) in anhydrous CH2Cl2
(15 mL) was added, and the stirring was continued at 2788C
for 1 h before NEt3 (15 mL) was added at the same
temperature. After stirring at 08C for 30 min and then at
room temperature for 30 min, water (30 mL) was added.
The organic layer was washed with 2 M aqueous HCl,
saturated aqueous NaHCO3 and brine, then dried over
MgSO4. Removal of the drying agent and the solvent under
reduced pressure gave the crude aldehyde, which was used
without further purification to the next step.
t
s, CH3), 1.36 (3H, s, CH3), 0.9 (9H, s, Bu-Si), 0.11 (6H,
s, CH3–Si–CH3). EIMS (m/z, %): 361 (Mþ2Me, 30.4),
261 (38.7), 185 (62.3), 117 (85.3), 101 (100.0), 59 (52.1).
IR (film): 3492, 2935, 1381, 1257, 1215, 1069,
To a vigorously stirred solution of aldehyde obtained above
and bromopropyne (1.8 mL, 27.9 mmol) in 60 mL of
anhydrous DMF–Et2O (1:1) under nitrogen, was slowly
added activated zinc dust (1.8 g, 27.6 mmol) in portions.
The resulting mixture was stirred for 2 h at room
temperature, then poured into saturated aqueous NH4Cl
and extracted with Et2O (50 mL£3). The combined organic
layers were dried over MgSO4, filtered and concentrated.
The residue was purified by column chromatography on
silica gel (PE/EA¼4:1) to afford 10 (3.14 g, 77%).
837 cm21
.
1.1.8. 4-O-Methyoxymethyl-1-O-[(t-Butyl)dimethylsilyl]-
2,3:5,6-di-O-isopropylidene-D-mannitol (9c). To
solution of 9b (6.6 g, 17.5 mmol) in anhydrous CH2Cl2
a
i
(30 mL) at 08C, were added Pr2NEt (9.2 mL, 54.6 mmol)
and MOMCl (4.0 mL, 51 mmol). The mixture was stirred
overnight at rt, then diluted with Et2O (100 mL), washed
with H2O, saturated aqueous NH4Cl, and brine, dried over
MgSO4. The solution was concentrated under reduced
pressure, and then the residue was purified by column
chromatography on silica gel (PE/EA¼5:1) to give 9c
(6.8 g, 92%). [a]D25¼þ19.4 (c, 1.93, CHCl3). 1H NMR
(400 MHz, CDCl3): d 4.83 (2H, s, OCH2O), 4.21 (1H, m,
OCH), 4.12 (1H, m, OCH), 4.1–4.0 (4H, m, OCH), 3.85
(1H, dd, J¼10.5, 7.0 Hz, OCH), 3.72 (1H, dd, J¼10.5,
4.7 Hz, OCH), 3.42 (3H, s, OCH3), 1.45 (3H, s, CH3), 1.40
(3H, s, CH3), 1.35 (3H, s, CH3), 1.34 (3H, s, CH3), 0.9 (9H,
[a]2D5¼6.9 (c, 1.5, CHCl3). H NMR (400 MHz, CDCl3): d
1
4.95 (1H, d, J¼6.6 Hz, OCH2O), 4.81 (1H, d, J¼6.6 Hz,
OCH2O), 4.33 (1H, t, J¼4.1 Hz, OCH), 4.23 (1H, m, OCH),
4.20 (1H, dd, J¼8.1, 4.1 Hz), 4.14 (1H, t, J¼7.1 Hz, OCH),
4.07 (1H, dd, J¼8.4, 6.3 Hz, OCH), 4.03 (1H, m, OCH),
4.02 (1H, t, J¼8.1 Hz, OCH), 3.44 (3H, s, OCH3), 3.34 (1H,
bd, J¼5.4 Hz, OH), 2.68 (1H, dt, J¼16.8, 3.0 Hz, –CHH–),
2.44 (1H, ddd, J¼16.8, 6.9, 2.7 Hz, –CHH–), 2.06 (1H, t,
J¼2.7 Hz, u–H), 1.44 (3H, s, CH3), 1.43 (3H, s, CH3), 1.36
(3H, s, CH3), 1.34 (3H, s, CH3). EIMS (m/z, %): 329
(Mþ2Me, 18.3), 313 (14.7), 255 (34.9), 101 (79.2), 45
(100.0). IR (film): 3449, 3287, 2987, 1371, 1218, 1084,
1033 cm21. Elemental analysis for C17H27O8 Calcd: C
59.29, H 8.19; Found: C 59.23, H 8.16.
t
s, Bu-Si), 0.1 (6H, s, CH3–Si–CH3). EIMS (m/z, %): 405
(Mþ2Me, 9.1), 331 (24.8), 305 (8.4), 185 (65.1), 101
(96.2), 45 (100.0). IR (film): 2956, 2934, 1380, 1253, 1218,
1032, 837 cm21. Elemental analysis for C20H40O7Si Calcd:
C 57.14, H 9.52; Found: C 57.40, H 9.42.
1.1.11. 4-O-[(t-Butyl)dimethylsilyl]-7-O-methyoxy-
methyl-1,2,3-trideoxy-5,6:8,9-di-O-isopropylidene-D-
erythro-D-manno-1-yno-nonitol (12). This compound was
obtained in 84% yield using the procedure as described for
9b. [a]2D5¼263.1 (c, 0.7, CHCl3). 1H NMR (400 MHz,
CDCl3): d 4.98 (1H, d, J¼6.8 Hz, OCH2O), 4.70 (1H, d,
J¼6.8 Hz, OCH2O), 4.45 (1H, dt, J¼9.0, 3.8 Hz, OCH),
4.24 (1H, dd, J¼9.0, 6.6 Hz, OCH), 4.12 (2H, m, OCH),
4.03 (3H, m, OCH), 3.38 (3H, s, OCH3), 2.58 (2H, m, CH2),
2.00 (1H, t, J¼2.6 Hz, u–H), 1.47 (3H, s, CH3), 1.38 (3H,
1.1.9. 4-O-Methyoxymethyl-2,3:5,6-di-O-isopropylidene-
D-mannitol (9d). To a solution of 9c (6.8 g, 16.2 mmol) in
THF (50 mL) at 08C, was added TBAF (1 M solution in
THF, 16 mL). After stirring for 2 h at room temperature, the
mixture was diluted with Et2O, washed with H2O and brine,
dried over MgSO4, and then concentrated under reduced
pressure, the residue was purified by column chromato-
graphy on silica gel (PE/EA¼1:1) to give 9d (4.5 g, 92%).
[a]2D5¼þ103.3 (c, 2.1, CHCl3). 1H NMR (400 MHz,

L.-S. Li, Y.-L. Wu / Tetrahedron 58 (2002) 9049–9054
9053
s, CH3), 1.35 (3H, s, CH3), 1.33 (3H, s, CH3), 0.92 (9H, s,
SitBt), 0.21 (3H, s, SiCH3), 0.20 (3H, s, SiCH3). EIMS (m/z,
%): 443 (Mþ2Me, 12.0), 369 (4.9), 215 (58.9), 101 (65.1),
73 (94.1), 45 (100.0). IR (film): 3284, 2933, 1370, 1253,
1157, 1086, 1031, 838 cm21. Elemental analysis for
C23H42O7Si Calcd: C 60.26, H 9.24; Found: C 60.00, H
9.04.
Elemental analysis for C21H30O14 Calcd: C 49.80, H 5.93;
Found: C 50.07, H 6.17.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (grant No. 29790126, 29872049), the
Chinese Academy of Sciences (KJ 95-A1-504), and the
State Ministry of Science and Technology (970211006-6,
G2000077502). We also express our appreciation to Dr
Yikang Wu and Dr Zhu-Jun Yao for their helpful
discussion.
1.1.12. 4-O-[(t-Butyl)dimethylsilyl]-7-O-methyoxy-
methyl-1-bromo-1,2,3-trideoxy-5,6:8,9-di-O-isopropyl-
idene-D-erythro-D-manno-1-yno-nonitol
compound was obtained in 87% yield using the procedure
(13).
This
1
as described for 6. [a]2D5¼256.0 (c, 0.6, CHCl3). H NMR
(400 MHz, CDCl3): d 4.98 (1H, d, J¼6.9 Hz, OCH2O), 4.69
(1H, d, J¼6.9 Hz, OCH2O), 4.43 (1H, dt, J¼8.4, 3.9 Hz,
OCH), 4.17 (1H, dd, J¼8.8, 6.1 Hz, OCH), 4.12 (2H, m,
OCH), 4.02 (3H, m, OCH), 3.37 (3H, s, OCH3), 2.64 (1H,
dd, J¼17.2, 3.6 Hz, CHH), 2.55 (1H, dd, J¼17.1, 4.3 Hz,
CHH), 1.47 (3H, s, CH3), 1.38 (3H, s, CH3), 1.35 (3H, s,
CH3), 1.34 (3H, s, CH3), 0.91 (9H, s, SitBt), 0.20 (3H, s,
SiCH3), 0.17 (3H, s, SiCH3). EIMS (m/z, %): 523 (Mþ2Me,
10.1), 521 (Mþ2Me, 9.6), 449 (17.4), 447 (17.6), 333
(10.8), 331 (10.5), 101 (67.2), 73 (81.7), 45 (100.0). IR
References
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OCH2O), 4.74 (1H, m), 4.70 (1H, d, J¼6.7 Hz, OCH2O),
4.44 (1H, dd, J¼6.3, 2.0 Hz, OCH), 4.13 (3H, s, OCH), 4.05
(1H, dd, J¼8.2, 6.2 Hz, OCH), 3.95 (2H, m, OCH), 3.85
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SiCH3). EIMS (m/z, %): 505 (Mþ2Me, 5.8), 373 (6.1), 245
(34.1), 159 (49.8), 101 (71.0), 45 (100.0). IR (film): 2956,
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1.1.14. Methyl 4,6,7,8,9-penta-O-acetyl-2,5-anhydro-3-
deoxy-2-methoxyl-D-erythro-D-mannofuranos-2-uloso-
nate (15). This compound was obtained in 75% yield using
the procedure as described for 8. [a]2D5¼26.4 (c, 0.97,
CHCl3). 1H NMR (300 MHz, CDCl3): d 5.50 (1H, dd,
J¼8.7, 2.5 Hz, OCH), 5.32 (1H, dd, J¼8.0, 2.4 Hz, OCH),
5.26 (1H, dt, J¼6.6, 2.0 Hz, OCH), 5.11 (1H, ddd, J¼8.4,
6.8, 2.8 Hz, OCH), 4.28 (1H, dd, J¼8.0, 1.3 Hz, OCH), 4.25
(1H, dd, J¼12.5, 2.8 Hz, OCH), 4.08 (1H, m, OCH), 3.83
(3H, s, OCH3), 3.35 (3H, s, OCH3), 2.64 (1H, dd, J¼15.2,
6.5 Hz, CHH), 2.45 (1H, dd, J¼15.2, 2.2 Hz, CHH), 2.14
(3H, s, CH3COO), 2.13 (3H, s, CH3COO), 2.10 (3H, s,
CH3COO), 2.05 (3H, s, CH3COO), 2.00 (3H, s, CH3COO).
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169.4, 168.8, 107.3, 84.2, 74.3, 69.3, 68.5, 68.3, 62.2, 52.7,
43.0, 21.0, 20.9, 20.8, 20.7, 20.6. EIMS (m/z, %): 506 (Mþ),
475 (4.2), 447 (53.4), 157 (34.6), 43 (100.0). IR (film):
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